Amino Acid Conjugates of Quetiapine, Process for Making and Using the Same

ABSTRACT

The presently described technology provides a novel class of prodrugs of quetiapine that can be synthesized by chemically conjugating amino acids to quetiapine. The present technology also provides methods of treating patients, pharmaceutical compositions and methods of synthesizing conjugates of the present technology.

RELATED APPLICATIONS

This application claims priority to and benefit from U.S. ProvisionalApplication Ser. No. 61/291,576, filed on Dec. 31, 2009, the content ofwhich is incorporated herein by reference in its entirety.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[Not Applicable]

BACKGROUND OF THE INVENTION

Quetiapine has been used in the treatment of severe mental illness inapproximately 70 countries including the US, Canada, most WesternEuropean countries, and Japan. Quetiapine is a dibenzothiazepinederivative with a relatively broad receptor binding profile. It hasmajor affinity to cerebral serotonergic (5-HT_(2A)), histaminergic (H1),and dopaminergic D₁ and D₂ receptors, moderate affinity to α₁- andα₂-adrenergic receptors, and minor affinity to muscarinergic M1receptors; it demonstrates a substantial selectivity for the limbicsystem. This receptor avidity profile with relatively higher affinityfor the 5-HT_(2A) receptor compared to the D₂ receptor is considered tobe, at least in part responsible for the antipsychotic characteristicsand low incidence of extrapyramidal side-effects of quetiapine.

The efficacy of quetiapine in reducing positive and negative symptoms ofschizophrenia has been proven in several clinical trials withplacebo-controlled comparators. Quetiapine has also demonstrated robustefficacy for treatment of cognitive, anxious-depressive, and aggressivesymptoms in schizophrenia. Quetiapine has also proven efficacy andtolerability in the treatment of moderate to severe manic episodes, andin the treatment of juveniles with oppositional-defiant or conductdisorders, and in the treatment of the geriatric population withdementia. Data indicate that quetiapine is also effective in thetreatment of bipolar depressive symptoms without increasing the risk oftriggering manic episodes, and in the treatment of borderlinepersonality disorder. In comparison with other atypical antipsychotics,quetiapine has a favorable side-effect profile.

In clinical trials, only small insignificant prolongations of the QTinterval were observed. Weight-gain liabilities and new-onset metabolicside-effects occupy a middle-ground among newer antipsychotics. As aresult of its efficacy and tolerability profile, quetiapine has becomewell established in the treatment of schizophrenia and other psychiatricdisorders.

Recently though, in addition to large interindividual variability andweight gain, reports surfaced on treatment emergent diabetes (TED),associated with chronic administration of quetiapine. Additionally, thetherapeutical dose of quetiapine is relatively high, forcing theproduction of pharmaceutical compositions with relatively highconcentrations of the active ingredient (up to 60%). Making tablets ofsuch a high concentration of the active pharmaceutical ingredient (API)is difficult, particularly due to the bad tabletting properties of theAPI.

An advantageous alternative would therefore be to improve the drug'sbioavailability, leading to an improved formulation that can lower thetotal necessary therapeutical dose and/or reduce side-effects such asTED and/or weight gain, and avoid the need for repeated administration.That formulation would help maintain regimen adherence by otherwisereluctant psychiatric patients.

BRIEF SUMMARY OF THE INVENTION

The present technology is directed to a novel class of prodrugs ofquetiapine that can be synthesized by chemically conjugating amino acidsto quetiapine. The chemical bond between these two moieties isestablished in one aspect, by reacting a primary hydroxyl functionalityof quetiapine or any one of its active metabolites and/or derivatives,with the carboxyl group of the amino acids, thereby creating acarboxylic ester conjugate.

In one embodiment, the invention provides a composition for treating apsychiatric disorder such as schizophrenia, bipolar disorder,obsessive-compulsive disorder, post-traumatic stress disorder, restlesslegs syndrome, autism, alcoholism, depression, insomnia or Tourettesyndrome in a subject, comprising a conjugate of2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol(quetiapine, QTP) or an active metabolite and/or active derivativethereof; and a standard amino acid such as an aliphatic or aromaticamino acid, non-standard amino acid or synthetic amino acid, a saltthereof, or a combination thereof. In another embodiment, thecomposition is formulated for oral or rectal administration whereinquetiapine or its active metabolite and/or active derivative thereofsuch as 7-hydroxy-N-desalkyl-quetiapine (7-OH-norQTP;4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazine and a standardamino acid such as an aromatic or aliphatic amino acids, non-standardamino acid or synthetic amino acid, a salt thereof, a derivative thereofor their combination is present in the composition in an amount of about1-2000 mg/dose based on equimolar weight of unconjugated quetiapine, orunconjugated active metabolite and/or active derivative thereof. Oraladministration is carried out in certain embodiments using a tablet,capsule, caplet, pill, troche, lozenge, liquid solution, suspension,elixir, or oral thin film (OTF).

In another embodiment, the invention provides quetiapine or its activemetabolite, conjugated to a standard amino acid, i.e., valine asrepresented by any one of the structures of formulas I-IV:

a pharmaceutically acceptable salt thereof such as a phosphate salt, aderivative thereof or their combination.

In one embodiment, the invention provides quetiapine or its activemetabolite, conjugated to a standard amino acid i.e., phenylalanine asrepresented by any one of the structures of formulas V-VIII:

a pharmaceutically acceptable salt thereof such as a hydrochloride salt,phosphate salt, mesylate salt or a besylate salt, a derivative thereofor their combination.

In another embodiment, the invention provides a method of conjugatingquetiapine or its active metabolite and/or active derivative thereofsuch as 7-hydroxy-quetiapine (7-OH-QTP) and a standard amino acid suchas an aromatic or aliphatic amino acids, non-standard amino acid such ashomoarginine or synthetic amino acid, comprising the steps of: in thepresence of a base such as 4-methylmorpholine (NMM),4-(dimethylamino)pyridine (DMAP), attaching an amine-protected aminoacid such as an aliphatic or aromatic amino acid to quetiapine or itsactive metabolite and/or active derivative, whereby the amine moiety isprotected with tert-butyloxycarbonyl (Boc) in one embodiment; followedby deprotecting the amine-protected amino acid moiety, alone or eithersequentially or simultaneously with deprotecting the amino acid sidechain that may be protected as well, thereby conjugating quetiapine orits active metabolite and/or active derivative thereof and an aminoacid.

In one embodiment, the invention provides a method of increasing therelative bioavailability of quetiapine or its active metabolite and/oractive derivative thereof such as N-desalkyl-quetiapine (norQTP),7-OH-norQTP or 7-OH-QTP, comprising the step of conjugating thequetiapine or the active metabolite and/or active derivative thereof toa standard amino acid such as an aromatic or aliphatic amino acids,non-standard amino acid such as homoarginine or synthetic amino acid,thereby modulating the hydrophobicity, solubility, improving absorption,altering metabolic pathways or their combination, resulting in certainembodiments, in a higher C_(max) and/or AUC and/or longer or similarT_(max) values produced by unconjugated quetiapine when administered atequimolar doses. Increased bioavailability may also result in: reducedinterindividual variability in plasma concentrations; decrease thenumber and/or amount of active, inactive, toxic or non-toxicmetabolites; and increase the number and/or amount of active metabolitesproduced by unconjugated quetiapine or its active metabolite and/oractive derivative thereof.

In another embodiment, the invention provides a method of treating apsychiatric disorder requiring the binding of dopamine receptor(s),serotonin receptor(s), or histamine receptor(s) or a combination thereofin a subject such as human or mammal, comprising the step of orally orrectally administering to the subject a composition comprising atherapeutically effective amount of about 1-2000 mg/dose based onequimolar weight of unconjugated API of quetiapine or its activemetabolite and/or active derivative thereof such asN-desalkyl-quetiapine, 7-hydroxy-N-desalkyl-quetiapine, or7-hydroxy-quetiapine, conjugated to a standard amino acid such as anaromatic or aliphatic amino acids, non-standard amino acid or syntheticamino acid, a pharmaceutically acceptable salt or derivative thereof,thereby binding a dopamine receptor, a serotonin receptor, histaminereceptor or any combination permutation thereof. In one embodiment, theinvention provides a method of treating schizophrenia or bipolardisorder in a subject in need thereof, comprising the step ofadministering to the subject a composition comprising a therapeuticallyeffective amount of a quetiapine or its active metabolite and/or activederivative thereof such as N-desalkyl-quetiapine,7-hydroxy-N-desalkyl-quetiapine, or 7-hydroxy-quetiapine, conjugated toan amino acid, a pharmaceutically acceptable salt such as a phosphatesalt, or derivative thereof, thereby binding to a dopamine receptor, aserotonin receptor, or both and treating schizophrenia or bipolardisorder.

In one embodiment, the invention provides a method of reducing weightgain resulting from chronic or acute administration of quetiapine in asubject, comprising the step of orally or rectally administering to thesubject a composition comprising therapeutically effective amount ofabout 1-2000 mg/dose based on equimolar weight of unconjugated API of aquetiapine or its active metabolite and/or active derivative thereofsuch as N-desalkyl-quetiapine, 7-hydroxy-N-desalkyl-quetiapine, or7-hydroxy-quetiapine, conjugated to a standard amino acid such as anaromatic or aliphatic amino acids, non-standard amino acid such ashomoarginine or synthetic amino acid, a pharmaceutically acceptable saltthereof such as a phosphate salt, or a derivative thereof, therebymodulating leptin and/or gherlin levels in the subject and reducing,decreasing and/or inhibiting weight gain in the subject.

In one embodiment, the invention provides a method of reducing weightgain resulting from chronic or acute administration of quetiapine in asubject, comprising the step of orally or rectally administering to thesubject a composition comprising a therapeutically effective amount ofabout 1-2000 mg/dose based on equimolar weight of unconjugated API of aquetiapine or its active metabolite and/or active derivative thereofsuch as N-desalkyl-quetiapine, 7-hydroxy-N-desalkyl-quetiapine, or7-hydroxy-quetiapine, conjugated to a standard amino acid such as anaromatic or aliphatic amino acids, non-standard amino acid such ashomoarginine or synthetic amino acid, a pharmaceutically acceptable saltthereof such as a phosphate salt, or a derivative thereof, therebyaltering the metabolism of quetiapine, its metabolite(s) and/orderivative(s) resulting in reduced binding to histamine receptors.

In another embodiment, the invention provides for the use of atherapeutically effective amount of a conjugate of quetiapine, itsactive metabolite and/or active derivative and/or their combination; anda standard, non-standard and/or synthetic amino acid and theircombination; in a medicament for the treatment of a disorder associatedwith serotonin, dopamine or histamine dysfunction in a subject in needthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be better understood from a reading of the followingdetailed description taken together with the figures and examplesprovided herein wherein like reference designators are used to designatelike elements or findings, and in which:

FIG. 1 shows general structure of standard amino acids;

FIG. 2 shows general structure of non-standard amino acids;

FIG. 3 shows synthetic amino acids;

FIG. 4 shows the oral PK profile of quetiapine released fromvaline-quetiapine compared to an equimolar dose of quetiapinedihydrochloride in rats;

FIG. 5 shows the oral PK profiles of quetiapine released fromβ-alanine-quetiapine, phenylalanine-quetiapine and lysine-quetiapinecompared to an equimolar dose of quetiapine dihydrochloride in rats;

FIG. 6 shows the oral PK profiles of quetiapine released fromtyrosine-quetiapine, leucine-quetiapine and aspartate-quetiapinecompared to an equimolar dose of quetiapine dihydrochloride in rats;

FIG. 7 shows a schematic of the process of synthesis of thevaline-quetiapine conjugate;

FIG. 8 shows embodiments of valine conjugates; and

FIG. 9 shows embodiments of phenylalanine conjugates.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention is directed to quetiapine conjugatecompositions, their synthesis and use. In another embodiment, theinvention is directed to quetiapine conjugates with standard,non-standard or synthetic amino acids, their syntheses and use intherapeutic compositions for the treatment of psychiatric disorders.

Quetiapine:

is an atypical antipsychotic in the sub-class of multi-actingreceptor-targeted antipsychotics (MARTA). Quetiapine exhibits antagonistactivity at the dopamine D₂ and D₁ receptors, the serotonin 5-HT₂receptor, the adrenergic α₁ and α₂ receptors and the histamine H₁receptor. While the modulation of the dopamine and serotonin receptorsare thought to be responsible for the therapeutic activity ofquetiapine, its affinity to the histamine and adrenergic receptors maybe the cause of some of its side-effects, particularly its somnolent andhypotensive effects.

Quetiapine is currently approved for the following indications:

-   -   Acute and chronic treatment of schizophrenia.    -   Acute depressive episodes associated with bipolar disorder.    -   Acute manic or mixed episodes associated with bipolar I disorder        as monotherapy and as an adjunct to lithium or divalproex        therapy.    -   Chronic treatment of bipolar I disorder as adjunct therapy to        lithium or divalproex.

Quetiapine has also shown acceptable efficacy in some off-labelindications that include obsessive-compulsive disorder, post-traumaticstress disorder, restless legs syndrome, autism, alcoholism, depressionand Tourette syndrome. It has been used as sedative for patients withsleep or anxiety disorders.

In one embodiment, the compositions comprising the prodrugs providedherein may be administered for the treatment of schizophrenia or bipolardisorder or for any condition that may require the blocking of dopamineor serotonin receptors.

The term “prodrug”, as used herein, refers in one embodiment to ametabolic precursor of a compound of the conjugated quetiapine providedherein, which is pharmaceutically acceptable. A prodrug may be inactivewhen administered to a subject but is converted in vivo to an activecompound. In one embodiment, the term “active metabolite”, refers to ametabolic product of quetiapine that is pharmaceutically and/orpharmacologically beneficial and/or effective. Prodrugs and activemetabolites may be determined using techniques known in the art.Prodrugs and active metabolites of a compound may be identified usingroutine techniques known in the art. In another embodiment, the term“active metabolite” refers to a metabolic product of quetiapine that iseffective for ameliorating, treating or preventing schizophrenia,bipolar disorder, obsessive-compulsive disorder, post-traumatic stressdisorder, restless legs syndrome, autism, alcoholism, depression,insomnia or Tourette syndrome.

Prodrugs are often useful because, in some embodiments, they may beeasier to administer or process than the parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent isnot. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. An embodiment of a prodrug would bean amino acid bonded to a primary hydroxyl group where the amino acid ismetabolized to reveal the active moiety. In certain embodiments, upon invivo administration, a prodrug is chemically converted to thebiologically, pharmaceutically or therapeutically more active form ofthe compound. In certain embodiments, a prodrug is enzymaticallymetabolized by one or more steps or processes to the biologically,pharmaceutically or therapeutically active form of the compound. Toproduce a prodrug, a pharmaceutically active compound is modified suchthat the active compound will be regenerated upon in vivoadministration. The prodrug is designed to alter the metabolism or thetransport characteristics of a drug in certain embodiments, to maskside-effects or toxicity, to improve the flavor of a drug or to alterother characteristics or properties of a drug in other discreteembodiments. By virtue of knowledge of pharmacodynamic processes anddrug metabolism in vivo, those of skill in this art, once apharmaceutically active compound is known, can design prodrugs of thecompound.

In another embodiment, the term “active metabolite” refers to abiologically active derivative of a compound that is formed when thecompound is metabolized. The term “metabolized,” refers in oneembodiment to the sum of the processes (including, but not limited to,hydrolytic reactions and reactions catalyzed by enzymes, such as,oxidation reactions, de-esterification reactions and/or proteolyticreactions) by which a particular substance is changed by an organism.Thus, enzymes may produce specific structural alterations to a compound.In one embodiment, cytochrome P450 catalyzes a variety of oxidative andreductive reactions while some isoforms, such as CYP3A4 are involved inde-esterification. Further information on metabolism may be obtainedfrom The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill(1996). Metabolites of the compounds disclosed herein can be identifiedeither by administration of compounds to a host under conditionsallowing for the determination of activity by the metabolite andanalysis of tissue samples from the host, or by incubation of compoundswith hepatic cells in vitro and analysis of the resulting compounds.Both methods are well known in the art. In some embodiments, a compoundis metabolized to pharmacologically active metabolites.

In another embodiment, amino acids conjugated to quetiapine or itsactive metabolite and/or derivative create ester prodrugs that canrelease the active antipsychotic. The prodrugs provided herein alter thepharmacology and/or metabolism of quetiapine its active metaboliteand/or derivative. As a result; by choosing suitable amino acids, thebioavailability of quetiapine is increased. In one embodiment, theside-effect profile and interindividual variability in plasmaconcentrations of the active are improved:

In one embodiment, provided herein is a novel class of prodrugs ofquetiapine its active metabolite and/or derivative, which is synthesizedby chemically conjugating amino acids to quetiapine its activemetabolite and/or derivative. The chemical bond between these twomoieties is established by reacting the primary hydroxyl functionalityof quetiapine, its active metabolite and/or derivative or non-bindingelectrons with the carboxyl group of the amino acids, thereby creatingan ester conjugate.

Accordingly and in another embodiment, provided herein is a compositionfor treating a psychiatric disorder in a subject, comprising a conjugateof2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol(quetiapine) its active metabolite and/or derivative and an amino acid,a salt thereof, a derivative thereof or their combination.

All amino acids have a core structure containing an amino group, acarboxyl group and a distinctive side chain. The carbon atom attached tothe carboxyl group is called the α-carbon. In α-amino acids both theamino and carboxyl group are attached to the α-carbon. In amino acidswith a carbon side chain attached to the α-carbon, the carbons arelabeled in the order of α, β, γ, δ, ε, etc. Amino acids with the aminogroup attached to a carbon other than the α-carbon are respectivelycalled β-amino acids, γ-amino acids, δ-amino acids and so forth. Aminoacids can be either D or L isomers. This invention includes compoundsobtained by conjugation of quetiapine to L and/or D isomers of aminoacids including but not limited to α-, β-, γ-, δ-, ε-amino acids,standard amino acids, non-standard amino acids, natural amino acids andsynthetic (unnatural/non-natural) amino acids.

Depending on the side chain of the amino acids conjugated to quetiapineor its active metabolite, the prodrug formed can be either neutral inone aspect of the invention, or free acid, free base or pharmaceuticallyacceptable anionic or cationic salt forms or salt mixtures with anyratio between positive and negative components in other discreteaspects. These salt forms include, but are not limited to: acetate,L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate,citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide,hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate,L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate,D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate,gluceptate, D-glucuronate, hybenzate, isethionate, malonate,methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate,tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate,ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate,hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate,furate, fusidate, galactarate (mucate), galacturonate, gallate,gentisate, glutamate, glutamate, glutarate, glycerophosphate, heptanoate(enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide,xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate,myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate,propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate,tannate, terephthalate, thiosalicylate, tribrophenate, valerate,valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate,esylate, glycolate, thiocyanate, and undecylenate. In one embodiment,composition for treating a psychiatric disorder in a subject, comprisinga conjugate of2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol(quetiapine) its active metabolite and/or derivative; and an amino acidare in the form of a phosphate salt.

In the compositions and methods described herein, the synthesizedprodrugs are designed to breakdown enzymatically or otherwise in vivo toquetiapine, its active metabolites and/or derivatives and the respectiveamino acids or their metabolites. Preferably, the amino acids of thepresent technology are Generally Regarded As Safe (GRAS) or non-toxic atthe concentrations released into the systemic circulation.

The amino acids used in the compositions and methods described herein,can be broadly classified in one of the following categories: standard(proteinogenic) amino acids; non-standard amino acids; and synthetic(unnatural/non-natural) amino acids.

Standard Amino Acids

Standard amino acids or proteinogenic amino acids include but are notlimited to the currently known 22 amino acids that make up the monomericunits of proteins and are encoded in the standard genetic code. Standardamino acids include alanine, arginine, asparagine, aspartic acid,cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, proline, pyrrolysine,selenocysteine, serine, threonine, tryptophan, tyrosine and valine.These amino acids have the general structure shown in FIG. 1, where Rrepresents the side chain on the α-carbon. In one embodiment, thecompositions provided herein, which are used in the methods provided,comprise quetiapine or its antipsychotic-active metabolites, conjugatedto a standard amino acid, wherein the standard amino acid is alanine,arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine,glycine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine,tryptophan, tyrosine or valine, their derivatives and pharmaceuticallyacceptable salts. Accordingly and in one embodiment, the amino acidconjugated to quetiapine or its active metabolite, used in thecompositions and methods described herein, is an aliphatic or aromaticamino acid wherein the aliphatic amino acid is glycine, leucine,isoleucine, proline, valine, methionine or alanine and/or, in anotherembodiment the aromatic amino acid is histidine, phenylalanine,tryptophan or tyrosine.

Non-Standard Amino Acids

Non-standard amino acids can be found in proteins created by chemicalmodifications of standard amino acids already incorporated in theproteins. This group also includes amino acids that are not found inproteins but are still present in living organisms. Non-standard aminoacids occur mostly as intermediates in metabolic pathways of standardamino acids and are not encoded by the standard genetic code. Examplesof non-standard amino acids include but are not limited to ornithine,homoarginine, citrulline, homocitrulline, homoserine, theanine,γ-aminobutyric acid, sarcosine, cartinine, 2-aminoadipic acid,pantothenic acid, taurine, hypotaurine, lanthionine, thiocysteine,cystathionine, homocysteine, β-amino acids such as β-alanine,β-aminoisobutyric acid, β-leucine, β-lysine, β-arginine, β-tyrosine,β-phenylalanine, isoserine, β-glutamic acid, β-tyrosine, β-dopa(3,4-dihydroxy-L-phenylalanine), α,α-disubstituted amino acids such as2-aminoisobutyric acid, isovaline, di-n-ethylglycine, N-methyl acidssuch as N-methyl-alanine, L-abrine, hydroxy-amino acids such as4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine,4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, cyclic amino acids such as1-aminocyclopropyl-1-carboxylic acid, azetidine-2-carboxylic acid andpipecolic acid (FIG. 2).

In one embodiment, the compositions provided herein, which are used inthe methods provided, comprise quetiapine or its antipsychotic-activemetabolites, conjugated to a non-standard amino acid, wherein thenon-standard amino acid is ornithine, homoarginine, citrulline,homocitrulline, homoserine, theanine, γ-aminobutyric acid, sarcosine,cartinine, 2-aminoadipic acid, pantothenic acid, taurine, hypotaurine,lanthionine, thiocysteine, cystathionine, homocysteine, β-amino acidssuch as β-alanine, β-aminoisobutyric acid, β-leucine, β-lysine,β-arginine, β-tyrosine, β-phenylalanine, isoserine, β-glutamic acid,β-tyrosine, β-dopa (3,4-dihydroxy-L-phenylalanine), α,α-disubstitutedamino acids such as 2-aminoisobutyric acid, isovaline,di-n-ethylglycine, N-methyl acids such as N-methyl-alanine, L-abrine,hydroxy-amino acids such as 4-hydroxyproline, 5-hydroxylysine,3-hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, cyclicamino acids such as 1-aminocyclopropyl-1-carboxylic acid,azetidine-2-carboxylic acid or pipecolic acid, their derivatives andpharmaceutically acceptable salts.

Synthetic Amino Acids

Synthetic amino acids do not occur in nature and are preparedsynthetically. In another embodiment, the compositions provided herein,which are used in the methods provided, comprise quetiapine or itsantipsychotic-active metabolites, conjugated to a non-standard aminoacid that includes but is not limited to allylglycine,cyclohexylglycine, N-(4-hydroxyphenyl)glycine, N-(chloroacetyl)glyclineester, 2-(trifluoromethyl)-phenylalanine,4-(hydroxymethyl)-phenylalanine, 4-amino-phenylalanine,2-chlorophenylglycine, 3-guanidino propionic acid, 3,4-dehydro-proline,2,3-diaminobenzoic acid, 2-amino-3-chlorobenzoic acid,2-amino-5-fluorobenzoic acid, allo-isoleucine, tert-leucine,3-phenylserine, isoserine, 3-aminopentanoic acid, 2-amino-octanedioicacid, 4-chloro-β-phenylalanine, β-homoproline, β-homoalanine,3-amino-3-(3-methoxyphenyl)propionic acid, N-isobutyryl-cysteine,3-amino-tyrosine, 5-methyl-tryptophan, 2,3-diaminopropionic acid,5-aminovaleric acid, and 4-(dimethylamino)cinnamic acid (FIG. 3).

In one embodiment, the compositions provided herein, which are used inthe methods provided, comprise quetiapine or its antipsychotic-activemetabolites, conjugated to a synthetic amino acid, wherein the syntheticamino acid is allylglycine, cyclohexylglycine,N-(4-hydroxyphenyl)glycine, N-(chloroacetyl)glycline ester,2-(trifluoromethyl)-phenylalanine, 4-(hydroxymethyl)-phenylalanine,4-amino-phenylalanine, 2-chlorophenylglycine, 3-guanidino propionicacid, 3,4-dehydro-proline, 2,3-diaminobenzoic acid,2-amino-3-chlorobenzoic acid, 2-amino-5-fluorobenzoic acid,allo-isoleucine, tert-leucine, 3-phenylserine, isoserine,3-aminopentanoic acid, 2-amino-octanedioic acid,4-chloro-β-phenylalanine, β-homoproline, β-homoalanine,3-amino-3-(3-methoxyphenyl)propionic acid, N-isobutyryl-cysteine,3-amino-tyrosine, 5-methyl-tryptophan, 2,3-diaminopropionic acid,5-aminovaleric acid, or 4-(dimethylamino)cinnamic acid, their derivativeor pharmaceutically acceptable salt and their combination.

In one aspect of the invention any of the abovementioned amino acids;standard (proteinogenic) amino acids; non-standard amino acids; andsynthetic (unnatural/non-natural) amino acids are used either alone orin combination in the compositions and methods described herein.Accordingly and in one embodiment, provided herein is a composition fortreating a psychiatric disorder in a subject, comprising a conjugate of2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol(quetiapine), its active metabolite and/or derivative and theircombination; and a standard amino acid, a non-standard amino acid, or asynthetic amino acid; a salt thereof, a derivative thereof or theircombination.

In another embodiment, the amino acid conjugated to quetiapine, itsactive metabolite and/or derivative and their combination, used in thecompositions and methods described herein, is an aliphatic amino acid,such as glycine in one embodiment. In other embodiments the aliphaticamino acids used in the compositions and methods described herein areleucine, isoleucine, valine, proline, methionine or alanine each adiscrete embodiment of the aliphatic amino acids used in the conjugatesof quetiapine, its active metabolite and/or derivative and theircombination provided herein.

In one embodiment, the active metabolite of quetiapine isN-desalkyl-quetiapine (norQTP,4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazine):

a major active human plasma metabolite of quetiapine, which has shownin-vitro antagonistic activity on multiple brain neurotransmitterreceptors and in particular on serotonergic (5-HT_(2A)), noradrenergic(α₁-adrenoreceptor) and the noradrenergic transporter, thus having inanother embodiment, a positive influence on mood. Likewise,N-desalkyl-quetiapine has a high affinity for the histamine H₁ receptorand moderate affinities for the norepinephrine reuptake transporter(NET), the serotonin 5-HT_(1E), 5-HT_(2A), 5-HT_(2B), 5-HT₇ receptors,the α_(1B)-adrenergic receptor, and the M₁, M₃, and M₅ muscarinicreceptors. In one embodiment, N-desalkyl-quetiapine has about 100-foldhigher avidity for inhibiting human NET than quetiapine itself.Additionally, N-desalkyl-quetiapine is 10-fold more potent and moreefficacious than quetiapine at the 5-HT_(1A) receptor.N-desalkyl-quetiapine is an antagonist at 5-HT_(2A), 5-HT_(2B),5-HT_(2C), α_(1A), α_(1D), α_(2A), α_(2C), H₁, M₁, M₃, and M₅ receptors,with a moderate affinity for the norepinephrine reuptake inhibitortransporter (NET) and partial 5-HT1_(A) agonism, indicating asignificant antidepressant effects. In one embodiment, the compositionsprovided herein, which in another embodiment are used in the methodsprovided herein comprise the N-desalkyl-quetiapine, conjugated to astandard, non-standard or synthetic amino acid, without the presence ofquetiapine.

In one embodiment, the active metabolite of quetiapine is7-hydroxy-quetiapine(2-(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol):

another active human plasma metabolite of quetiapine having intrinsicreceptor activity. 7-hydroxy-quetiapine has been shown to occupydopamine D₂ and serotonin 5-HT₂ receptors. In one embodiment, thecompositions provided herein, which in another embodiment are used inthe methods provided herein comprise 7-hydroxy-quetiapine, conjugated toa standard, non-standard or synthetic amino acid, without the presenceof quetiapine.

In another embodiment, the term “derivative” refers to having asubstituent bonded to the quetiapine or its active metabolite such ashalogenated derivatives ether derivatives, acid derivatives, amidederivatives, ester derivatives and the like. Methods of preparingderivatives such as ether derivatives in one embodiment, comprisecoupling of the corresponding alcohols. In another embodiment, the term“derivative” refers to a chemical compound related structurally toquetiapine or its active metabolites and is therapeutically derivablefrom it. In one embodiment, the term “active derivative” refers to aderivative as defined herein, which is accountable for a desiredbiological effect. Accordingly, an active derivative of quetiapine willhave in one embodiment an antipsychotic activity, or an antidepressantactivity and the like in other embodiments of desired biological effect.

In one embodiment, the active derivative of quetiapine is2-chloro-N-desalkyl-quetiapine(2-chloro-11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine);

a derivative of norQTP, which, due to its similar structure to the knownantidepressant Amoxapine (sold as ASENDIN, ASENDIS, DEFANYL, DEMOLOX,MOXADIL), is thought to possess similar activity as a norepinephrinreuptake inhibitorand and/or as a partial 5-HT agonist. In oneembodiment, the compositions provided herein, which in anotherembodiment is used in the methods provided herein comprise2-chloro-N-desalkyl-quetiapine, conjugated to a standard, non-standardor synthetic amino acid and/or its pharmaceutically acceptable salt,without the presence of quetiapine.

In one embodiment, the active derivative of quetiapine is4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazine,7-hydroxy-N-desalkyl-quetiapine (7-OH-norQTP);

a derivative of norQTP, which, due to its similar structure to the knownactive quetiapine metabolite 7-hydroxy-quetiapine, is thought to possesssimilar activity. In one embodiment, the compositions provided herein,which in another embodiment is used in the methods provided hereincomprise 7-hydroxy-N-desalkyl-quetiapine, conjugated to a standard,non-standard or synthetic amino acid and/or its pharmaceuticallyacceptable salt, without the presence of quetiapine.

In one embodiment, the amino acid is valine and the conjugate is2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylL-valine,2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylD-valine,2-(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylL-valine,2-(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylD-valine,(R)-2-amino-1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-3-methylbutan-1-one,(S)-2-amino-1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-3-methylbutan-1-one,(R)-2-amino-1-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-3-methylbutan-1-one,(S)-2-amino-1-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-3-methylbutan-1-one;their derivative, pharmaceutically acceptable salt or their combination.

In one embodiment, the amino acid is phenylalanine and the conjugate is2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylL-phenylalanine,2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylD-phenylalanine,2-(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylL-phenylalanine,2-(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylD-phenylalanine,(R)-2-amino-1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-3-phenylpropan-1-one,(S)-2-amino-1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-3-phenylpropan-1-one,(R)-2-amino-1-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-3-phenylpropan-1-one,(S)-2-amino-1-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-3-phenylpropan-1-one;their derivative, pharmaceutically acceptable salt or their combination.

Amino acid ester prodrugs of quetiapine, its active metabolite and/orderivative and their combination as described above can be administeredorally and the parent drug is released after hydrolysis in the body.Typically these prodrugs are easily recognized by physiological systemsbecause the attached amino acid moieties are either naturally occurringor mimic naturally occurring compounds. As a result, the prodrugsprovided herein are hydrolyzed chemically, enzymatically or by acombination of chemical and enzymatic processes; and release quetiapine.In another embodiment the compositions comprising the prodrug describedherein, are either pharmacologically inactive, have pharmacologicalactivity that is limited or different from the parent drug, andconsequently, in certain embodiments, may follow a metabolic pathwaythat differs from quetiapine.

In another embodiment, the term “prodrug” refers to a precursor orderivative form of a pharmaceutically active substance that impartshigher bioavailability to quetiapine compared to the parent drug and iscapable of being enzymatically or hydrolytically activated or convertedinto the more active parent form. In one embodiment, the compositionscomprising the prodrug described herein would release quetiapine, itsactive metabolite and/or derivative and their combination—in a similarfashion to free or unconjugated API. In another embodiment, thecompositions comprising the prodrug described herein would releasequetiapine, its active metabolite and/or derivative or theircombination—in a controlled or sustained manner without the need of anextended release formulation.

In a further embodiment, the compositions comprising the prodrugdescribed herein would have increased absorption over unmodifiedquetiapine. In another embodiment, the compositions comprising theprodrug described herein would have improved water solubility over freequetiapine. In another embodiment, the increased absorption overunmodified quetiapine, or improved water solubility over freequetiapine, provide for a better bioavailability of quetiapine referringto a higher area under the curve (AUC) or having higher circulatingplasma concentrations.

In another embodiment, conjugating quetiapine, its therapeuticallyactive metabolite(s) and/or derivative(s) to a standard, non standard orsynthetic amino acid as well as their pharmaceutically accepted salts,alter the API metabolism, thereby resulting in a maximum plasmaconcentration (C_(max)) value of released quetiapine that is higher thanthe C_(max) value produced by unconjugated quetiapine when administeredat equimolar doses, or in generating an AUC value of released quetiapinethat is higher than the AUC value produced by unconjugated quetiapine inanother embodiment, or in generating both a C_(max) and an AUC value ofreleased quetiapine that is higher than the C_(max) and AUC valuesproduced by unconjugated quetiapine, or in generating a time afteradministration at which C_(max) occurs (T_(max)) value of releasedquetiapine its active metabolite and/or derivative and their combinationthat is longer than the T_(max) value produced by unconjugatedquetiapine, or in generating a T_(max) value of released quetiapine thatis similar to the T_(max) value produced by unconjugated quetiapine,when administered at equimolar or therapeutically equivalent doses.

In one embodiment, the term “therapeutically equivalent” refers to apreparation where its therapeutic effect is equivalent. In anotherembodiment, the term “therapeutically equivalent” refers tocircumstances where conjugated quetiapine, its therapeutically activemetabolite(s) and/or derivative(s) and their pharmaceutically acceptablesalts as described herein, are administered in amounts which give riseto the same therapeutic effect as does the specified amount ofunconjugated quetiapine, its therapeutically active metabolite(s) and/orderivative(s) and their pharmaceutically acceptable salts. It is routinefor those skilled in the art to determine therapeutically equivalentamounts or dosages (see e.g. Mahatthanatrakul et al., Int J ClinPharmacol Ther. 2008 Sep.; 46(9):489-96. and/or Woods, S. W. J ClinPsychiatry. 2003 Jun.; 64(6):663-7)

In another embodiment, the terms “therapeutically effective”, or“therapeutic effect”, refers to that amount of the conjugated orunconjugated API being administered, which will relieve to some extentone or more of the symptoms of the disorder or disease being treated. Inanother embodiment, the term “therapeutically effective dose” refers tothe amount of a compound of the compositions described herein that, whenadministered to an individual is effective to at least partially treat adisorder, disease or condition from which the individual is suffering,or to at least partially ameliorate a symptom of such disorder, diseaseor condition. As is understood in the art, the therapeutically effectiveamount of a given compound will depend at least in part upon, the modeof administration, any carrier or vehicle (e.g., solution, emulsion,etc.) employed, the specific disorder or condition, other medicationstaken by the individual and the specific characteristics of theindividual to whom the compound is to be administered (age, weight,condition, sex, etc.).

In yet another embodiment, the compositions comprising the prodrugdescribed herein would have increased bioavailability over unconjugatedquetiapine. This may allow for administration of a lower dose with equalor improved therapeutic effect, but with fewer and/or less severeside-effects when compared to unmodified quetiapine, thereby improvingthe safety and/or tolerability profile of the drug. Common side-effectsassociated with quetiapine include sedation, numbing, constipation,dizziness, dry mouth, lightheadedness, nasal congestion, sore throat,stomach pain or upset, tiredness, vomiting, weakness, weight gain,hyperlipidemia, hypotension, hyperglycemia and more. In one embodiment,the use of the compositions described herein results in elimination,amelioration, reduction, delay of onset or improvement in commonside-effects associated with chronic or acute administration ofquetiapine, wherein the common side-effects include but are not limitedto sedation, constipation: dizziness, dry mouth, lightheadedness, nasalcongestion, sore throat, stomach pain or upset, tiredness, vomiting,weakness, weight gain, hyperlipidemia, hypotension, hyperglycemia ortheir combination.

In another embodiment, the compositions comprising the prodrug describedherein would reduce weight gain when compared to unconjugatedquetiapine. Accordingly and in one embodiment, the invention provides amethod of reducing weight gain resulting from chronic or acuteadministration of quetiapine in a subject, comprising the step of orallyor rectally administering to the subject a composition comprising atherapeutically effective amount of about 1-2000 mg/dose based onequimolar weight of unconjugated quetiapine; of quetiapine or its activemetabolite and/or active derivative thereof such as7-hydroxy-N-desalkyl-quetiapine, or 7-hydroxy-quetiapine, conjugated toa standard amino acid such as an aromatic or aliphatic amino acids,non-standard amino acid such as homoarginine or synthetic amino acid, apharmaceutically acceptable salt such as a phosphate salt or derivativethereof, thereby modulating leptin and/or gherlin levels, or in anotherembodiment, altering the metabolism of quetiapine, its metabolite(s)and/or derivative(s), resulting in reduced binding to histaminereceptor(s) in the subject and thereby eliminating, reducing, delaying,decreasing and/or inhibiting weight gain in the subject.

In one embodiment, chronic oral administration of quetiapine, a knownorexigenic, for a period of 6 weeks causes about 37% increase in leptinrelease. In another embodiment, conjugating an active metabolite and/orderivative of quetiapine to a standard, non-standard or synthetic aminoacid will decrease the release of leptin and/or gherlin, resulting incertain embodiments in lower weight gain or lower increase in body-massindex (BMI). Since gherlin regulates the release of leptin in certainembodiment, and is released in response to fasting and cachexia,ingestion of aliphatic and aromatic amino acid conjugates of quetiapinewill decrease its release, resulting in lower weight gain.

In one embodiment, provided herein is a method of reducing weight gainresulting from chronic or acute administration of quetiapine in asubject, comprising the step of orally or rectally administering to thesubject a composition comprising a therapeutically effective amount ofabout 1-2000 mg/dose based on equimolar weight of unconjugated API of aquetiapine or its active metabolite and/or active derivative thereofsuch as N-desalkyl-quetiapine, 7-hydroxy-N-desalkyl-quetiapine, or7-hydroxy-quetiapine, conjugated to a standard amino acid such as anaromatic or aliphatic amino acids, non-standard amino acid such ashomoarginine or synthetic amino acid, a pharmaceutically acceptable saltthereof such as a phosphate salt, or a derivative thereof, therebyaltering the metabolism of quetiapine, its metabolite(s) and/orderivative(s) resulting in reduced binding to histamine receptors.

In one embodiment H₁-histamine receptor antagonism increases feeding inrodents. Additionally, in another embodiment, depletion of neuronalhistamine increases feeding. Likewise H₁-knockout mice are relativelyresistant to the anorectic actions of leptin, and are prone to obesitywhen placed on high-fat diets. These results indicate that in oneembodiment, H₁— histamine receptors modulate feeding behavior via aleptin-dependent mechanism. In another embodiment, H₁ affinity is apredictor of weight gain in chronic administration of antipsychotic. Inone embodiment, the conjugated quetiapine, its therapeutically effectivemetabolite(s) and/or derivative(s) reduces the affinity of quetiapine toH₁ receptor, raising the K_(m) in one embodiment above 11 nM.

In another embodiment, the compositions comprising the prodrug describedherein would generate a C_(max) value of released quetiapine that ishigher than the C_(max) value produced by unconjugated quetiapine whenadministered at equimolar doses. In a further embodiment, thecompositions comprising the prodrug described herein would generate anAUC value of released quetiapine that is higher than the AUC valueproduced by unconjugated quetiapine when administered at equimolardoses. In yet another embodiment, the compositions comprising theprodrug described herein would generate both a C_(max) and an AUC valueof released quetiapine that is higher than the C_(max) and AUC valuesproduced by unconjugated quetiapine when administered at equimolardoses.

In another embodiment the compositions comprising the prodrug describedherein would generate a T_(max) value of released quetiapine its activemetabolite and/or derivative and their combination—that is longer thanthe T_(max) value produced by unconjugated quetiapine when administeredat equimolar doses. In another embodiment the compositions comprisingthe prodrug described herein would generate a T_(max) value of releasedquetiapine that is similar to the T_(max) value produced by unconjugatedquetiapine, when administered at equimolar doses.

In another embodiment, the compositions comprising the prodrug describedherein would have reduced interindividual variability either due toincreased bioavailability in one aspect, or due to a modified metabolicpathway in another aspect, or due to a combination of both in yetanother aspect.

In another embodiment, the compositions comprising the prodrug describedherein would alter the metabolic pathway of the released quetiapine whencompared to unmodified quetiapine. This new metabolism may decreaseinterindividual variability and/or reduce side-effects associated withunconjugated quetiapine or any of its metabolites, pharmaceuticallyacceptable salts thereof, derivatives thereof or their combination.

In yet another embodiment, the compositions comprising the prodrugdescribed herein would decrease the number and/or amount ofmetabolites—active, inactive, toxic or non-toxic—produced by unmodifiedquetiapine. This may decrease interindividual variability and/or reduceside-effects associated with the administration of unconjugatedquetiapine.

In a further embodiment, the compositions comprising the prodrugdescribed herein would increase the amount of active metabolites whencompared to unmodified quetiapine. This may improve the therapeuticefficacy of the parent drug.

Although quetiapine is not a controlled substance, there have beenincreasing reports of its misuse via oral, intranasal, and intravenousroutes to exploit its potent sedative and anxiolytic properties. Some ofits street names include “quell”, “baby heroin” and “Susie-Q”. In someembodiments, the compositions comprising the prodrug described hereinmay not be hydrolyzed efficiently when administered by non-oral routes.As a result, these prodrugs may generate plasma concentrations ofreleased quetiapine that are lower when compared to free quetiapine whenadministered intravenously (“injected”) or intranasally (“snorted”).

In one embodiment, provided herein is a quetiapine or its activemetabolite, conjugated to the standard amino acid valine as representedby any one of the structures of formulas I-IV:

a pharmaceutically acceptable salt thereof, a derivative thereof ortheir combination.

In another embodiment, provided herein is a quetiapine or its activemetabolite, conjugated to the standard amino acid phenylalanine, asrepresented by any one of the structures of formulas V-VIII:

a pharmaceutically acceptable salt thereof, a derivative thereof ortheir combination.

In one embodiment, the salt of the conjugate of quetiapine or an activemetabolite and/or derivative thereof and a standard, non-standard and orsynthetic amino acid, such as any one of the structures represented byformulas I-VI hereinabove, is a hydrochloride salt, a hydrobromide salt,a hydroiodide salt, a sulfate, a phosphate, an organic acid salt, anitrate, or a mixture thereof. In another embodiment, the organic acidis a mesylate salt, a besylate salt, a tosylate salt, a benzoate, anoxalate, a fumarate, a triflate, a citrate, a malate, or a tartarate.

Formulation Examples

The prodrugs provided in the compositions and methods herein areprimarily geared towards oral dosage forms. These dosage forms includebut are not limited to tablet, capsule, caplet, troche, lozenge, powder,suspension, syrup, solution or oral thin film (OTF). Embodiments of oraladministration forms are capsule, tablet, solutions and OTF. The filmdosage forms provide an inexpensive, convenient and immediate method fordelivery of the compositions described herein without the undesirableaspects associated with certain oral or nasal delivery methods, whileproviding versatility, safety and patient comfort. Any effective edible“thin film” or “strip” may be used in accordance with the presentinvention. Unless otherwise specified or required by the context, theedible films of the present invention may be manufactured in anyeffective manner.

In certain embodiments, the film layer can be produced using a highlywater-soluble polymer comprising a natural or synthetic water-solublepolymer. The polymer preferably has good film moldability, produces asoft flexible film, and is safe for human consumption. In anotherembodiment, one such polymer can be a water-soluble cellulose derivativelike hydroxypropyl cellulose (HPC), methyl cellulose, hydroxypropylalkylcellulose, carboxymethyl cellulose or the salt of carboxymethylcellulose or the polymer can comprise an acrylic acid copolymer or itssodium, potassium or ammonium salt. The acrylic acid copolymer or itssalt can be combined with methacrylic acid, styrene or vinyl type ofether as a comonomer, poly vinyl alcohol, poly vinyl pyrrolidone,polyalkylene blycol, hydroxy propyl starch, alginic acid or its salt,poly-saccharide or its derivatives such as trangacanth, bum gelatin,collagen, denatured gelatin, and collagen treated with succinic acid oranhydrous phthalic acid. In another embodiment the powder matrix maycomprise as an adhesives: poorly water-soluble cellulose derivativesincluding ethyl cellulose, cellulose acetate and butyl cellulose;shellac; higher fatty acids including steric acid and palmitic acid. Thefollowing can also, without limitation, be used to produce the filmlayer: pullulan, maltodextrin, pectin, alginates, carrageenan, guar gum,other gelatins, etc. The-thickness of the film layer can vary asdesired, but typically is in the range of 0.01 mm to 3.00 mm, preferably0.03 mm to 1.00 mm. In one embodiment, the standard, non-standard, orsynthetic amino acid used in the conjugates provided herein will beaffected by the composition of the OTF.

Solid dosage forms can include the following types of excipients:antiadherents, binders, coatings, disintegrants, fillers, flavors,colors, glidants, lubricants, preservatives, sorbents and sweeteners.

For oral administration, the conjugates can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the conjugates providedherein to be formulated as tablets, pills, dragees, capsules, liquids,gels, syrups, slurries, suspensions, and the like, for oral ingestion bya patient. Pharmacological preparations for oral use can be made using asolid excipient, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries ifdesired, to obtain tablets or dragee cores. Suitable excipients are, incertain embodiments, fillers such as sugars, including lactose, sucrose,manioc, or sorbitol; cellulose preparations such as, for example, maizestarch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarbomethylcellulose and/or physiologically acceptable polymers such aspoly(vinylpyrrolidone) (PVP). If desired, in certain embodimentsdisintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

Dragee cores may be provided with suitable coatings. For this purpose,concentrated sugar solutions may be used which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, titanium dioxide, lacquer solutions and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g., sterile, pyrogen-free water, before use. The conjugatesprovided herein may also be formulated in rectal compositions such assuppositories or retention enemas, using, e.g., conventional suppositorybases such as cocoa butter or other glycerides.

Pharmaceutical compositions, which can be used orally, include push-fitcapsules made of gelatin as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules may contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive compounds may be dissolved or suspended in suitable liquids, suchas fatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers may be added. All formulations for oraladministration should be in dosages suitable for the chosen route ofadministration.

Quetiapine was originally launched as an immediate release product(Seroquel®) with the following dosage strengths per tablet: 25 mg, 50mg, 100 mg, 200 mg and 300 mg. Recommended daily doses typically rangefrom 150-800 mg depending on indication and individual patienttitration. In another embodiment, quetiapine is available in an extendedrelease formulation (Seroquel XR®) with dosage strengths of 50 mg, 150mg, 200 mg, 300 mg and 400 mg per tablet. Typical daily doses range from300-800 mg.

In one embodiment, the conjugate of quetiapine, its antipsychotic-activemetabolite and/or active derivatives; and a standard, non-standard, orsynthetic amino acid used in the compositions provided herein, a saltthereof, a derivative thereof or their combination is present in anamount of between about 1 mg and 2000 mg per dose form. In anotherembodiment, conjugates of quetiapine or its antipsychotic-activemetabolite and/or active derivatives thereof, their salt orpharmaceutically acceptable salt are present in the compositionsprovided herein in an amount that is therapeutically effective. In oneembodiment, conjugates of quetiapine or its antipsychotic-activemetabolite and/or active derivatives thereof, their salt orpharmaceutically acceptable salt are present in the compositionsprovided herein in an amount of between about 150 and 800 mg per doseform. In one embodiment, conjugates of quetiapine or itsantipsychotic-active metabolite and/or active derivatives thereof, theirsalt or pharmaceutically acceptable salt are present in the compositionsprovided herein in an amount of between about 1 and 100 mg per doseform, or between about 100 and 200 mg/dose, or between about 200 and 300mg/dose, or between about 300 and 400 mg/dose, or between about 400 and500 mg/dose, or between about 500 and 600 mg/dose, or between about 600and 700 mg/dose, or between about 700 and 800 mg/dose, or between about800 and 900 mg/dose, or between about 900 and 1000 mg/dose, or betweenabout 350 and 400 mg/dose, or between about 20 and 30 mg/dose, orbetween about 50 and 150 mg/dose, or between about 1 and 375 mg/dose,each a discrete embodiment of the amount conjugates of quetiapine or itsantipsychotic-active metabolite and/or active derivatives thereof, theirsalt or pharmaceutically acceptable salt are present in the compositionsprovided herein. In one embodiment, conjugates of quetiapine or itsantipsychotic-active metabolite and/or active derivatives thereof, theirsalt or pharmaceutically acceptable salt are present in the compositionsprovided herein in an amount of between about 1000 and 2000 mg per doseform. In another embodiment, conjugates of quetiapine or itsantipsychotic-active metabolite and/or active derivatives thereof, theirsalt or pharmaceutically acceptable salt are present in the compositionsprovided herein in an amount of between about 1000 and 1250 mg per doseform, or between about 1250 and 1500 mg per dose form, or between about1500 and 1750 mg per dose form, or between about 1750 and 2000 mg perdose form, or between about 1000 and 1500 mg per dose form, or betweenabout 1500 and 2500 mg per dose form, in other discrete embodiments.

Doses of the amino acid-quetiapine conjugate prodrugs described hereincan be higher or lower than doses of unconjugated quetiapine dependingon their molecular weight, the respective weight-percentage ofquetiapine as part of the whole conjugate or conjugate salt and theirbioavailability (with respect to released quetiapine). Dose conversionfrom quetiapine fumarate to quetiapine prodrug are performed in oneembodiment, using the following formula:

Dose(QTP prodrug)=f_(BA)×[dose(QTP hemifumarate)×(molecular weight(QTPprodrug)/441.95 g/mol]

Wherein:

QTP=quetiapinef_(BA)=correction factor accounting for differences in bioavailabilitybetween unmodified quetiapine and the compositions comprising theprodrug described herein. This correction factor is specific for eachprodrug with f_(BA)≦1 in certain embodiments. In one embodiment, theconjugate of quetiapine, an active metabolite or derivative thereof anda standard, non-standard and/or synthetic amino acid, a salt thereof, aderivative thereof or their combination is present in an amountcalculated according to the formula provided herein, referred to as“equivalent dose” to certain unconjugated quetiapine doses.

Quetiapine is a dibenzothiazepine derivative. In pharmacokinetic studiesquetiapine is rapidly absorbed after oral administration, with mediantime to reach maximum observed plasma concentration ranging from 1 to 2hours. Absolute bioavailability is estimated at 9%, with a relativebioavailability from orally administered tablets compared with asolution of almost 100%. Administration with foods other than fattyfoods, has minimal effects on the absorption of the API. The drug isapproximately 83% bound to serum proteins. Linear pharmacokinetics areobserved in the clinical dose range (up to 375 mg twice daily). Theterminal half-life time for the drug's elimination is about 7 hours,with the primary route of elimination being through hepatic metabolism.

In one embodiment, the term “relative bioavailability” refers toAUC_((0-∞)) for a specific orally administered composition expressed asa percentage of AUC_((0-∞)) for an orally administered formulation ofthe active ingredient at the same dosage rate. The term “C_(max)” refersto the maximum observed blood plasma concentration or the maximum bloodplasma concentration calculated or estimated from a concentration/timecurve, and is expressed in units of ng/ml. The term “T_(max)” refers tothe time after administration at which C_(max) occurs, and is expressedin units of hours (h).

In one embodiment, the relative bioavailability of the compositionsdescribed herein is increased by between about 9 and 100% whenadministered orally compared with oral administration of unconjugatedquetiapine, an active metabolite and/or an active derivative thereof. Inanother embodiment, the relative bioavailability is increased by betweenabout 25 and 100%, or between about 50 and 100%, or between about 75 and100%, or between about 100 and 125%, or between about 125 and 150%, orbetween about 150 and 175%, or between about 175 and 200%, or betweenabout 9 and 25%, when administered orally compared with oraladministration of unconjugated quetiapine, an active metabolite and/oran active derivative thereof in other discrete embodiments.

Quetiapine is metabolised in one embodiment by cytochrome P450 (CYP) 3A4and/or 2D6 in certain other embodiments. Eleven metabolites wereidentified as formed through hepatic oxidation, with three of thosefound to be pharmacologically active. In one embodiment, the metabolitesare conjugated to the amino acids described herein and are administeredeither alone or in combination with the quetiapine conjugatescompositions described herein and used in the methods described.Accordingly, in one embodiment, provided herein is a composition fortreating a psychiatric disorder in a subject, comprising a conjugate of7-hydroxy-quetiapine (7-OH-QTP) represented by the structure of FormulaIX:

and an amino acid, a salt thereof, a derivative thereof or theircombination. In another embodiment, provided herein is a composition fortreating a psychiatric disorder in a subject, comprising a conjugate of7-hydroxy-N-desalkyl-quetiapine (7-OH-norQTP) represented by thestructure of Formula X:

and an amino acid, a salt thereof, a derivative thereof or theircombination. In another embodiment, provided herein is a composition fortreating a psychiatric disorder in a subject, comprising a conjugate ofN-desalkyl-quetiapine (norQTP) represented by the structure of FormulaXI:

and an amino acid, a salt thereof, a derivative thereof or theircombination.

In one embodiment, oral clearance of unconjugated quetiapine declineswith age. In another embodiment, relative bioavailability of aminoacid-quetiapine conjugates is higher at every age, thereby leading toreduced dosage for every indication and minimizing side-effects. Sincequetiapine is primarily metabolized by CYP3A4, dosage adjustment may benecessary in another embodiment when coadministered with phenyloin,thioridazine retinoic acid, rifampicin, ketoconazole, carbamazepine orother potent CYP3A4 agonists, antagonists or modulators. In oneembodiment, the choice of amino-acid conjugated to quetiapine willaffect the dosage adjustment necessary.

Advantages

Conjugation of quetiapine or its active metabolite and/or activederivative thereof to amino acids as described herein, has a number ofadvantages that may include:

-   -   1. Reduced interindividual variability in plasma concentrations        vs. free quetiapine    -   2. Increased bioavailability    -   3. Improved side-effect profile    -   4. Less potential for toxic metabolites    -   5. Less inactive metabolites    -   6. Improved solubility    -   7. Reduced potential for drug abuse

In one embodiment, the compositions comprising quetiapine conjugated toan amino acid, further comprise a carrier, excipient, lubricant, flowaid, processing aid or diluent, wherein said carrier, excipient,lubricant, flow aid, processing aid or diluent is a gum, starch, asugar, a cellulosic material, an acrylate, calcium carbonate, magnesiumoxide, talc, lactose monohydrate, magnesium stearate, colloidal siliconedioxide or mixtures thereof.

In another embodiment, the composition further comprises a binder, adisintegrant, a buffer, a protease inhibitor, a surfactant, asolubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, aviscosity increasing agent, a sweetener, a film forming agent, or anycombination thereof.

In one embodiment, the composition is a controlled release composition.In another embodiment, the composition is an immediate releasecomposition. In one embodiment, the composition is a liquid dosage form.In another embodiment, the composition is a solid dosage form.

In one embodiment, the term “pharmaceutically acceptable salts” embracessalts commonly used to form alkali metal salts and to form additionsalts of free acids or free bases. The nature of the salt is notcritical, provided that it is pharmaceutically acceptable. Suitablepharmaceutically acceptable acid addition salts of compounds of theamino acid-quetiapine conjugates described herein and/or theirmetabolites and derivatives, are prepared in another embodiment, from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic,phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic,toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic,β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitablepharmaceutically acceptable base addition salts include metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. All of these salts may be prepared byconventional means from the corresponding compound by reacting, inanother embodiment, the appropriate acid or base with the compound.

In one embodiment, the term “pharmaceutically acceptable carriers”includes, but is not limited to, 0.01-0.1M and preferably 0.05Mphosphate buffer, or in another embodiment 0.8% saline. Additionally,such pharmaceutically acceptable carriers may be in another embodimentaqueous or non-aqueous solutions, suspensions, and emulsions. Examplesof non-aqueous solvents are propylene glycol, polyethylene glycol,vegetable oils such as olive oil, and injectable organic esters such asethyl oleate. Aqueous carriers include water, alcoholic/aqueoussolutions, emulsions or suspensions, including saline and bufferedmedia. In one embodiment the level of phosphate buffer used as apharmaceutically acceptable carrier is between about 0.01 to about 0.1M,or between about 0.01 to about 0.09M in another embodiment, or betweenabout 0.01 to about 0.08M in another embodiment, or between about 0.01to about 0.07M in another embodiment, or between about 0.01 to about0.06M in another embodiment, or between about 0.01 to about 0.05M inanother embodiment, or between about 0.01 to about 0.04M in anotherembodiment, or between about 0.01 to about 0.03M in another embodiment,or between about 0.01 to about 0.02M in another embodiment, or betweenabout 0.01 to about 0.015 in another embodiment.

The pharmaceutical preparations comprising the compositions used in oneembodiment in the methods provided herein can be prepared by knowndissolving, mixing, granulating, or tablet-forming processes. For oraladministration, the active ingredients, or their physiologicallytolerated derivatives in another embodiment, such as salts, esters,N-oxides, and the like are mixed with additives customary for thispurpose, such as vehicles, stabilizers, or inert diluents, and convertedby customary methods into suitable forms for administration, such astablets, coated tablets, hard or soft gelatin capsules, aqueous,alcoholic or oily solutions. Examples of suitable inert vehicles areconventional tablet bases such as lactose, sucrose, or cornstarch incombination with binders such as acacia, cornstarch, gelatin, withdisintegrating agents such as cornstarch, potato starch, alginic acid,or with a lubricant such as stearic acid or magnesium stearate.

Examples of suitable oily vehicles or solvents are vegetable or animaloils such as sunflower oil or fish-liver oil. Preparations can beeffected both as dry and as wet granules. For parenteral administration(subcutaneous, intravenous, intraarterial, or intramuscular injection),the active ingredients or their physiologically tolerated derivativessuch as salts, esters, N-oxides, and the like are converted into asolution, suspension, or emulsion, if desired with the substancescustomary and, suitable for this purpose, for example, solubilizers orother auxiliaries. Examples are sterile liquids such as water forinjection and oils, with or without the addition of a surfactant andother pharmaceutically acceptable adjuvants. Illustrative oils are thoseof petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, or mineral oil. In general, water, saline,aqueous dextrose and related sugar solutions, and glycols such aspropylene glycols or polyethylene glycol are preferred liquid carriers,particularly for injectable solutions. In one embodiment, usingaliphatic or aromatic amino acids, increases solubility ordispersibility of quetiapine conjugates when compared to unconjugatedquetiapine, its active metabolite and/or derivative in the oily vehiclesdescribed herein.

In addition, the composition described in the embodiments providedherein, can contain minor amounts of auxiliary substances such aswetting or emulsifying agents, pH buffering agents which enhance theeffectiveness of the active ingredient.

The amino acid-quetiapine conjugate described herein is administered inanother embodiment, in a therapeutically effective amount. The actualamount administered, and the rate and time course of administration,will depend in one embodiment, on the nature and severity of thecondition being treated. Prescription of treatment, e.g., decisions ondosage, timing, etc., is within the responsibility of generalpractitioners or specialists, and typically takes account of thedisorder to be treated, the condition of the individual patient, thesite of delivery, the method of administration and other factors knownto practitioners. Examples of techniques and protocols can be found inRemington's Pharmaceutical Sciences.

The compositions of the present invention are formulated in oneembodiment for oral delivery, wherein the active compounds may beincorporated with excipients and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. The tablets, troches, pills, capsules and the like mayalso contain the following: a sweetening agent, such as sucrose, lactoseor saccharin that may be added or a flavoring agent, such as peppermint,oil of wintergreen, or cherry flavoring. When the dosage unit form is acapsule, it may contain, in addition to materials of the types describedhereinabove, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar, or both. Syrup of elixir may contain the active compound, sucroseas a sweetening agent, methyl and propylparabens as preservatives, a dyeand flavoring, such as cherry or orange flavor. In addition, the API maybe incorporated into sustained-release, pulsed release, controlledrelease or postponed release preparations and formulations.

In another embodiment, the term “dosage unit” or “dose” refers to theportion of a pharmaceutical composition that contains a single unit doseof the active ingredient. For purposes of the disclosure presentedherein, a dose unit can be in the form of a discrete article such as atablet, capsule or a suppository, or can be a measurable volume of asolution, suspension or the like containing a unit dose of the activeingredient. The term “unit dose” refers in one embodiment to an amountof active ingredient intended for a single oral administration to asubject for treatment of a psychiatric condition or disorder. Treatmentof a psychiatric condition or disorder, comprising mediating or bindingof a dopamine and/or serotonin and/or histamine receptor, may requireperiodic administration of unit doses of the compositions describedherein, for example one unit dose two or more times a day, one unit dosewith each meal, one unit dose every four hours or other interval, oronly one unit dose per day.

Controlled or sustained release compositions include formulations inlipophilic depots (e.g., fatty acids, waxes, oils). Also comprehended bythe invention are particulate compositions coated with polymers (e.g.,poloxamers or poloxamines).

In another embodiment, a controlled release system can be placed inproximity to the therapeutic target, i.e., the brain, thus requiringonly a fraction of the systemic dose (see, e.g., Goodson, in MedicalApplications of Controlled Release, supra, vol. 2, pp. 115-138 [1984]).Other controlled release systems are discussed in the review by Langer(Science 249:1527-1533 [1990]).

In one embodiment, the carriers for use within such compositions arebiocompatible, and/or biodegradable. In other embodiments, theformulation may provide a relatively constant level of release of oneactive component. In other embodiments, however, a more rapid rate ofrelease immediately upon administration may be desired. In otherembodiments, release of active compounds may be event-triggered. Theevents triggering the release of the active compounds may be the same inone embodiment, or different in another embodiment. Events triggeringthe release of the active components may be exposure to moisture, lowerpH or temperature threshold in other discrete embodiments. Theformulation of such compositions is well within the level of ordinaryskill in the art using known techniques. Illustrative carriers useful inthis regard include microparticles of poly(lactide-co-glycolide),polyacrylate, latex, starch, cellulose, dextran and the like. Otherillustrative postponed-release carriers include supramolecularbiovectors, which comprise a non-liquid hydrophilic core (e.g., across-linked polysaccharide or oligosaccharide) and, optionally, anexternal layer comprising an amphiphilic compound, such asphospholipids. The amount of active compound contained in oneembodiment, within a sustained release formulation depends upon the siteof administration, the rate and expected duration of release and thenature of the condition to be treated suppressed or inhibited.

In one embodiment, the term “administering” refers to bringing a subjectin contact with the compositions provided herein. For example, in oneembodiment, the compositions provided herein are suitable for oraladministration, whereby bringing the subject in contact with thecomposition comprises ingesting the compositions. A person skilled inthe art would readily recognize that the methods of bringing the subjectin contact with the compositions provided herein, will depend on manyvariables such as, without any intention to limit the modes ofadministration; age, pre-existing conditions, other agents administeredto the subject, the severity of symptoms, subject weight or propensityto gain weight, refraction to other medication and the like. In oneembodiment, provided herein are embodiments of methods for administeringthe compounds of the present invention to a subject, through anyappropriate route, as will be appreciated by one skilled in the art.

Methods of Synthesis

A general synthetic scheme for the synthesis of a prodrug of thisinvention typically consists of the following steps:

-   -   1. Protection of the amino acid, if applicable.    -   2. Activation of the carboxylic group, if not already in        activated form.    -   3. Addition of activated amino acid to quetiapine or vice versa        in the presence of base    -   4. Removal of amino acid protecting groups, if applicable.

Accordingly and in one embodiment, provided herein is a method ofconjugating quetiapine or an active metabolite and/or derivative thereofand an amino acid comprising the steps of: in the presence of a base,attaching an amine-protected amino acid to quetiapine or its activemetabolite; followed by deprotecting the amine-protected amino acidmoiety, thereby, creating a carboxylic ester between quetiapine or anactive metabolite and/or derivative thereof and a standard, non-standardor synthetic amino acid. An schematic of an exemplary process ofsynthesis of a valine-quetiapine conjugate is provided in FIG. 7.

The carboxylic acid group of the amino acid is activated in oneembodiment in order to react with quetiapine to produce appreciableamounts of conjugate. The amino acids can be activated in anotherembodiment, by synthesizing esters of N-hydroxy succinimide (NHS). Otheractivating agents include but are not limited to the following:N,N′-dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCI),N,N′-diisopropyl-carbodiimide (DIC), 1,1′-carbonyldiimidazole (CDI) orother carbodiimides;(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP),(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP) or other phosphonium-based reagents;O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), fluoro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (TFFH),N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (TSTU)or other ammonium-based reagents.

Accordingly and in one embodiment, provided herein is a method ofconjugating quetiapine or its active metabolite and/or active derivativethereof and an amino acid comprising the steps of: in the presence of abase, attaching an amine-protected amino acid to quetiapine or itsactive metabolite; followed by deprotecting the amine-protected aminoacid moiety, thereby conjugating quetiapine or an active metaboliteand/or derivative thereof and an amino acid. In one embodiment, theamine-protected amino acid further comprises a protected side chainresidue on the amino acid.

It may be necessary to attach one or more protecting groups to anyadditional reactive functional groups that may interfere with thecoupling to quetiapine. Any suitable protecting group may be useddepending on the type of functional group and reaction conditions. Theprotective group may be any of those commonly used in a process known bythose skilled in the art. In one embodiment a protective group is for anamino, thiol, hydroxy, phenol or carboxyl group used in commonpreparations of amino acids. Some protecting group examples include butare not limited to: acetyl (Ac), tert-butyloxycarbonyl (Boc),benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (Moz),9-fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (PMB),3,4 dimethoxybenzyl (DMPM), p-methozyphenyl (PMP), tosyl (Ts), or amides(like acetamides, pthalamides, etc). In another embodiment, the aminoacid residue protecting group is acetyl, propionyl, butyryl,phenylacetyl, benzoyl, toluoyl, POA, methoxycarbonyl, ethoxycarboryl,2,2,2-trichloro-ethoxycarbonyl, 2-iodoethoxycarbonyl,4-methoxybenzyloxycarbonyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl(Mtr), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) or2,2,5,7,8-pentamethyl-chroman-6-sulfonyl (Pmc).

In another embodiment, the protective group is not particularly limitedas long as it is a protective group known to protect the amino group orthe side chain group. Examples of useful protective groups are thosedescribed in T. W. Greene, “Protective groups in Organic Synthesis”, AWiley-Interscience Publication, John-Wiley & Sons, New York, 1981, pp.218-287. Specific examples include but are not limited to substitutedoxycarbonyl groups, such as lower alkyloxycarbonyl groups in anotherembodiment, i.e., C₂₋₇ straight-chain or branched-chain loweralkyloxycarbonyl groups. The protective group for carboxyl on the groupside chain is not specifically limited as long as it is a conventionalprotective group known to form an ester or an ether with a carboxylgroup. Examples are C₁₋₆ straight-chain or branched-chain substituted orunsubstituted lower alkyl groups such as methyl, ethyl, propyl, butyl,tert-butyl, hexyl and trichloroethyl; substituted or unsubstitutedaralkyl groups such as benzyl, p-nitrobenzyl, p-methoxybenzyl anddiphenylmethyl; acyloxyalkyl groups such as acetoxymethyl, acetoxyethyl,propionyloxyethyl, pivaloyloxypropyl, benzoyloxymethyl, benzoyloxyethyl,benzylcarbonyloxymethyl and cyclohexylcarbonyloxymethyl; alkoxyalkylgroups such as methoxymethyl, ethoxymethyl and benzyloxymethyl; andother groups such as tetrahydropyranyl, dimethylaminoethyl,dimethylchlorosilyl and trichlorosilyl. Preferred are substituted orunsubstituted alkyl groups and substituted or unsubstituted aralkylgroups.

A base may be required at any step of the synthesis of amino acidconjugates of quetiapine. Suitable bases include but are not limited to4-methylmorpholine (NMM), 4-(dimethylamino)pyridine (DMAP),N,N-diisopropylethylamine, lithium bis(trimethylsilyl)amide, lithiumdiisopropylamide (LDA), any alkali metal tert-butoxide (e.g., potassiumtert-butoxide), any alkali metal hydride (e.g., sodium hydride), anyalkali metal alkoxide (e.g., sodium methoxide), triethylamine or anyother tertiary amine.

An acid may be required to remove certain protecting groups. Suitableacids include but are not limited to hydrochloric acid, hydrobromicacid, hydrofluoric acid, hydriodic acid, sulfuric acid, phosphoric acid,trifluoroacetic acid, acetic acid, citric acid, methanesulfonic acid,p-toluenesulfonic acid and nitric acid.

Appropriate solvents that can be used for any reaction in the syntheticscheme of any amino acid conjugate of quetiapine include but are notlimited to: acetone, acetonitrile, butanol, chloroform, dichloromethane,dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, ethanol,ethyl acetate, diethyl ether, heptane, hexane, methanol, methyltert-butyl ether (MTBE), isopropanol, isopropyl acetate, diisopropylether, tetrahydrofuran, toluene, xylene or water.

In one embodiment, the step of deprotecting the amine-protected aminoacid moiety is preceded by a step of deprotecting the side chain on theamino acid. In another embodiment, the step of deprotecting theamine-protected amino acid, is done simultaneously with deprotecting theside chain on the amino acid. In another embodiment, the step ofdeprotecting the side chain is preceded by a step of deprotecting theamine-protected amino acid moiety.

In one embodiment, the compounds conjugated using the methods providedherein, are used in the compositions and methods described herein.Accordingly, and in another embodiment, provided herein is quetiapine,its active metabolite and/or derivative; conjugated to a standard,non-standard and/or synthetic amino acid synthesized by attaching anamine-protected amino acid in the presence of a base to quetiapine orits active metabolite and/or derivative; followed by deprotecting theamine-protected amino acid moiety, thereby conjugating quetiapine, anactive metabolite and/or an active derivative thereof and an amino acid.

In another embodiment, the protecting groups prevent undesired ordeleterious reactions from taking place at the alpha-amino group duringthe formation of a new carboxyl ester bond between the unprotectedcarboxyl group of the standard, non-standard and/or synthetic aminoacid; and the free non-binding electrons on the quetiapine, its activemetabolite and/or derivative. A series of chemical steps subsequentlyprotect the amino acid and prepare it for coupling to the quetiapine,its active metabolite and/or derivative without undesirable sidereactions. In one embodiment, “protecting” an acid prevents undesiredside or competing reactions, and “deprotecting” an acid makes itsfunctional group(s) available for a desired reaction and/or obtainingthe final conformation of the prodrug.

Deprotection is carried out in one embodiment with a mild base treatment(e.g., picrodine or piperidine, for a non-limiting example) fortemporary protective groups, while in another embodiment; permanentside-chain protecting groups are removed by moderate acidolysis (e.g.,trifluoroacetic acid (TFA) as a non-limiting example).

In one embodiment, the compositions described herein are used to carryout the methods provided herein.

In one embodiment, the psychiatric disorder sought to be treated usingthe compositions provided herein is bipolar disorder (BPD) and theinpatient receives conjugated quetiapine at an equimolar dose in theamount of 375 mg daily of unconjugated quetiapine, corresponding to adose of over 375 mg daily due to the higher bioavailability, or alteredmetabolism of the conjugated quetiapine as described herein, resultingin a larger difference and shorter duration in depressive symptoms onadmission and at discharge using the Beck-Rafaelsen Mania Scale (MAS)and/or the Montgomery Asberg depression rating scale (MADRS),respectively.

In another embodiment, the psychiatric disorder sought to be treatedusing the compositions provided herein is schizophrenia, and theinpatient receives conjugated quetiapine at an equimolar dose in theamount of 450 mg daily of unconjugated quetiapine, corresponding to adose of over 450 mg daily due to the higher bioavailability or alteredmetabolism of the conjugated quetiapine as described herein, resultingin a larger difference and shorter duration in psychotic symptoms onadmission and at discharge using Brief Psychiatric Rating Scale (BPRS),Clinical Global Impression (CGI), Positive And Negative Syndrome Scale(PANSS) and the like. Using the compositions described herein, resultsin another embodiment in increased interval between psychotic episodes,decrease in severity of the episode and a lesser loss in cognitiveabilities following an episode.

In one embodiment, provided herein is a method of treating a psychiatricdisorder requiring the binding of dopamine receptor, serotonin receptor,or both in a subject, comprising the step of administering to thesubject a composition comprising therapeutically effective amount ofquetiapine, an active metabolite and/or an active derivative thereof,conjugated to an amino acid, a pharmaceutically acceptable salt orderivative thereof, thereby binding to a dopamine receptor, a serotoninreceptor, or both.

In another embodiment, provided herein is a method of treatingschizophrenia or bipolar disorder in a subject in need thereof,comprising the step of administering to the subject a compositioncomprising therapeutically effective amount of quetiapine, an activemetabolite and/or an active derivative thereof, conjugated to an aminoacid, a pharmaceutically acceptable salt or derivative thereof, therebybinding to a dopamine receptor, a serotonin receptor, or both.

In another embodiment, due to the higher relative bioavailability theunit dose used for treating the disorders described herein, will beadjusted downward, leading to a decrease in number and severity ofside-effects.

In one embodiment, the disorder requiring the binding of dopaminereceptor(s), serotonin receptor(s), or both in a subject isobsessive-compulsive disorder (OCD), post-traumatic stress disorder(PTSD), restless legs syndrome, autism, alcoholism, depression,insomnia, hyperprolactinemia or Tourette syndrome.

By way of example, Restless Leg Syndrome (RLS) has been treated withnon-ergot dopamine agonists, with quetiapine showing remarkableefficacy. In one embodiment, provided herein is a method of treating RLSin a subject in need thereof, comprising the step of orallyadministering to the subject a therapeutically effective amount of acomposition comprising quetiapine, an active metabolite and/or activederivative thereof conjugated to a standard, non-standard and/orsynthetic amino acid, a pharmaceutically acceptable salt thereof ortheir combination.

Likewise and in another embodiment, post-traumatic stress disorder(PTSD) refers in one embodiment to a chronic mental illness, causingoccupational disability, psychiatric and medical morbidity and severepsychosocial distress. The prevalence of PTSD in the general populationin the U.S. in 2006 was estimated to be 7.8%. Core symptoms of PTSDinclude recurrent re-experiencing of the trauma in the form of intrusivememories, nightmares and flashbacks; avoidant behaviors; and autonomicarousal. In addition to the core PTSD symptoms, patients with PTSD alsoexhibit irritability, impulsivity, depression and aggression. PTSD isoften difficult to treat, with recent initiatives focusing on the roleof serotonin in the neuroregulation of PTSD. The neurotransmitterserotonin influences mood, aggression, arousal, anxiety, sleep,learning, nociception, fear and appetite. Likewise, dopamineneurotransmission dysfunction has been shown to be responsible forsymptoms such as paranoia, hallucinations, increased startle responseand their combination. Physiologically, the density of plateletserotonin-uptake sites, as determined by paroxetine binding, wassignificantly decreased in patients with PTSD, compared with normalcontrols. Clinical studies showed the benefits of treatment of PTSDsymptoms with a 5-HT_(1A) partial agonist, of which quetiapinemetabolite N-desalkyl-quetiapine is one.

In one embodiment, the term “treating” refers to abrogating,substantially inhibiting, slowing or reversing the progression of adisease, substantially ameliorating clinical symptoms of a disease orsubstantially preventing or delaying the appearance of clinical symptomsof a disease.

In one embodiment, the compositions provided herein, which in anotherembodiment are used in the methods described herein; are administered toa subject in need thereof as part of a combination therapy with othermedication that is specific for the indication sought to be treated. Aperson skilled in the art would readily recognize that combinationtherapy as described in the methods and compositions provided herein,could be administered either simultaneously or consecutively and so longas they are administered for the same indication, would be encompassedby the description provided herein.

Accordingly and in one embodiment lithium or divalproex in anotherembodiment are used in certain embodiments as adjunct therapies with thecompositions provided herein.

In one embodiment, provided herein is the use of a therapeuticallyeffective amount of a conjugate of quetiapine, its active metaboliteand/or active derivative; and a standard, non-standard and or syntheticamino acid in a medicament for the treatment of a disorder associatedwith serotonin, dopamine or histamine dysfunction in a subject in needthereof.

In the present specification, use of the singular includes the pluralexcept where specifically indicated.

In one embodiment, the term “subject” refers to a mammal including ahuman in need of therapy for, or susceptible to, a condition or itssequelae. The subject may include dogs, cats, pigs, cows, sheep, goats,horses, rats, and mice and humans. The term “subject” does not excludean individual that is normal in all respects.

The term “about” as used herein means in quantitative terms plus orminus 5%, or in another embodiment plus or minus 10%, or in anotherembodiment plus or minus 15%, or in another embodiment plus or minus20%.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way beconstrued, however, as limiting the broad scope of the invention.

EXAMPLES Example 1 Oral Pharmacokinetic Data

Plasma concentrations of quetiapine released from prodrug conjugates asdescribed herein were dosed as oral solutions in rats and compared to anequimolar solution of quetiapine dihydrochloride. Although thecommercial form of quetiapine (Seroquel®) is a fumarate salt, thedihydrochloride salt was used as comparator because the fumarate is notsoluble enough to be dosed efficiently via oral gavage in rats.

Generally and as shown in FIGS. 4-6, plasma concentrations of releasedquetiapine varied depending on the attached amino acid. For the providedexamples, the systemic exposure of released quetiapine ranged from99-175% (%-AUC compared to quetiapine dihydrochloride).Valine-quetiapine showed the highest relative %-AUC value of 175%.C_(max) values varied between 61-189% (%-C_(max) compared to quetiapinedihydrochloride) with valine-quetiapine producing the highest relative%-C_(max) value of 189%. T_(max) values were similar for all examples.

Example 2 General Synthesis of Amino Acid-Quetiapine Conjugates

A general synthetic scheme for the synthesis of a prodrug of thisinvention typically consists of the following steps:

-   -   1. Protection of the amino acid, if applicable.    -   2. Activation of the carboxylic group, if not already in        activated form.    -   3. Addition of activated amino acid to quetiapine or vice versa        in the presence of base    -   4. Removal of amino acid protecting groups, if applicable.

To a solution of quetiapine (1 mmol) in THF (10 mL) was added LiN(TMS)₂(1.5 mmol) at room temperature. The solution was stirred for 30 min. atroom temperature. N-protected amino acid succinimidyl ester (1.05 mmol)in THF (10 mL) was added dropwise. The mixture was stirred for anadditional 30 min. at room temperature, subsequently poured into anaqueous solution of ammonium chloride (200 mL) and extracted with EtOAc(2×200 mL). The organic layer was washed with aqueous NH₄Cl (2×100 mL)and brine (2×100 mL), dried over anhydrous Na₂SO₄ and evaporated todryness to yield the N-protected amino acid-quetiapine conjugate.

The protected intermediate (1 mmol) was stirred in 4 N HCl/dioxane (10mL) for 30 min. at room temperature and then concentrated to dryness toyield the respective hydrochloride salt of the amino acid conjugate ofquetiapine.

Example 3 Synthesis of Valine-Quetiapine Phosphate (Val-QTP.H₃PO₄)Boc-Val-QTP

To a solution of quetiapine free base 1 (7.66 g, 19.97 mmol) in THF (50mL) was added dropwise LiN(TMS)₂ (24.9 mL, 24.9 mmol) and the reactionmixture was stirred at room temperature for 30 min. A solution ofBoc-Val-OSu (6.9 g, 21.96 mmol) in THF (12 mL) was added dropwise over aperiod of 3-4 min. After 1 h, saturated aqueous NH₄Cl (150 mL) was addedand stirred for 15 mins. EtOAc (300 mL) was added to the reactionmixture and stirred for an additional 30 min. The EtOAc layer was washedwith citric acid solution [2% citric acid (100 mL)+brine (100 mL)] (2×),5% aq. NaHCO₃ (1×200 mL) and brine (1×200 mL). The organic phase wasdried over anhydrous Na₂SO₄ and evaporated to dryness to give theBoc-Val-QTP (11.09 g, 95%).

Val-QTP.3HCl

Boc-Val-QTP was dissolved in 1.25 M HCl in IPA (150 mL) and the reactionmixture was stirred at room temperature for 20 h. The volume of thereaction mixture was reduced to half and poured into IPAc (250 mL) whilestirring. The precipitate was filtered, washed with IPAc (2×) and driedto give Val-QTP.3HCl (11.01 g, 98%).

Alternate Method

Boc-Val-QTP (4.5 g, 7.7 mmol) was dissolved in IPA (25 mL) and to thissolution was added 5-6 N HCl in IPA (25 mL). The brown reaction mixturewas stirred overnight at room temperature. The reaction volume wasreduced to half and poured into IPAc (150 mL) while stirring. The whiteprecipitate was filtered, washed with IPAc and dried to giveVal-QTP.3HCl (4.2 g, 92%).

Val-QTP FB

Val-QTP.3HCl (6.4 g, 10.99 mmol) was dissolved in water (50 mL) and tothis solution was added saturated aq. NaHCO₃ (150 mL) followed by EtOAc(250 mL). The mixture was stirred for 1 h at room temperature. The EtOAclayer was washed with sat. NaHCO₃ (2×) and brine, dried over Na₂SO₄ andevaporated to dryness to give Val-QTP FB (5.8 g) as an oil.

Val-QTP.H₃PO₄

To a solution Val-QTP FB (5.8 g, 10.52 mmol) in IPA (50 mL) was addeddropwise 1 M H₃PO₄ solution (10.55 mL) in IPA. A white precipitateappeared after the addition. The reaction mixture was stirred for 30min. at room temperature. The suspension was diluted with IPAc (60 mL)and stirred for an additional 30 min. The white precipitate wasfiltered, washed with IPAc and dried to give Val-QTP.H₃PO₄ (4.05 g).

Several embodiments of exemplary valine conjugates of the presenttechnology are provided in FIG. 8.

Example 4 Synthesis of Phenylalanine-Quetiapine Trihydrochloride(Phe-QTP.3 HCl)

To a solution of quetiapine free base (0.23 g, 0.6 mmol) in THF (8 mL)was added dropwise LiN(TMS)₂ (0.96 mL, 0.96 mmol) and the reactionmixture was stirred for 30 min. at room temperature. A solution ofBoc-Phe-OSu (0.228 g, 0.63 mmol) in THF (4 mL) was added dropwise atroom temperature over a period of 5 min. After 2 h, the reaction wasquenched with aqueous NH₄Cl (50 mL) and stirred for 15 min. The reactionmixture was extracted with EtOAc. The EtOAc layer was washed with aq.NH₄Cl (2×50 mL), sat. aq. NaHCO₃ (1×50 mL) and brine. The organic phasewas dried over anhydrous Na₂SO₄ and evaporated to dryness to giveBoc-Phe-QTP (0.24 g).

Boc-Phe-QTP was dissolved in 4 N HCl/dioxane (12 mL) and the reactionmixture was stirred for 4 h at room temperature. Solvents wereevaporated and the residue was co-evaporated with IPAc and dried to givePhe-QTP-3HCl (0.25 g).

Several embodiments of exemplary phenylalanine conjugates of the presenttechnology are provided in FIG. 9.

Example 5 Synthesis of Aspartate-Quetiapine Trihydrochloride(Asp-QTP.3HCl)

To a solution of quetiapine free base (0.24 g, 0.62 mmol) in THF (8 mL)was added dropwise LiN(TMS)₂ (0.99 mL, 0.99 mmol) and the reactionmixture was stirred for 30 min. at room temperature. A solution ofBoc-Asp(O^(t)Bu)—OSu (0.254 g, 0.65 mmol) in THF (4 mL) was addeddropwise over a period of 5 min. After 3 h, the reaction was quenchedwith aqueous NH₄Cl (50 mL) and extracted with EtOAc (110 mL). The EtOAclayer was washed with 1% aq. NaHSO₄ (50 mL), sat. aq. NaHCO₃ (50 mL) andbrine. The organic phase was dried over anhydrous Na₂SO₄ and evaporatedto dryness to give Boc-Asp(O^(t)Bu)-QTP (0.265 g).

A solution of Boc-Asp(O^(t)Bu)—O-Que in 4 N HCl/dioxane (12 mL) wasstirred for 8 h at room temperature. Solvents were evaporated and theresidue was co-evaporated with IPAc and dried to give Asp-QTP.3HCl (0.26g).

Having described preferred embodiments of the invention with referenceto the accompanying drawings, it is to be understood that the inventionis not limited to the precise embodiments, and that various changes andmodifications may be effected therein by those skilled in the artwithout departing from the scope or spirit of the invention as definedin the appended claims.

1-134. (canceled)
 135. A composition for treating a psychiatric disorderin a subject, comprising a conjugate of2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol(quetiapine) or an active metabolite thereof and an amino acid, a saltthereof, a derivative thereof or their combination.
 136. The compositionof claim 135, wherein the amino acid is a standard amino acid, anon-standard amino acid, a natural amino acid, a synthetic amino acid ora combination thereof.
 137. The composition of claim 135, wherein theamino acid is valine and the conjugate is2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylL-valine,2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylD-valine, their active metabolites and/or derivatives, pharmaceuticallyacceptable salts or their combination.
 138. The composition of claim135, wherein the amino acid is phenylalanine and the conjugate is2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylL-phenylalanine,2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylD-phenylalanine, their active metabolites and/or derivatives,pharmaceutically acceptable salts or their combination.
 139. Thecomposition of claim 135, wherein the composition has a higher relativebioavailability than non-conjugated quetiapine when administered orally.140. The composition of claim 135, wherein the composition is formulatedfor oral or suppository administration.
 141. The composition of claim140, wherein the composition formulated for oral administration is atablet, capsule, caplet, pill, troche, lozenge, liquid solution,suspension, elixir or oral thin film.
 142. The composition of claim 135,wherein the conjugate of quetiapine or an active metabolite and/or anactive derivative thereof and an amino acid, a salt thereof, aderivative thereof or their combination is present in an amount ofbetween about 1 mg and 2000 mg per unit dose.
 143. The composition ofclaim 141, wherein the conjugate of quetiapine or an active metaboliteand/or an active derivative thereof and an amino acid, a salt thereof, aderivative thereof or their combination is present in an amount ofbetween about 150 and 800 mg per unit dose.
 144. The composition of anyone of claim 142 or 143, wherein the presence of quetiapine, an activemetabolite and/or an active derivative thereof is based on molarequivalent of unconjugated quetiapine or unconjugated active metabolitethereof.
 145. The composition of claim 135, wherein the psychiatricdisorder is schizophrenia, bipolar disorder, obsessive-compulsivedisorder, post-traumatic stress disorder, restless legs syndrome,autism, alcoholism, depression, insomnia or Tourette syndrome.
 146. Thecomposition of claim 135, wherein the subject is a human or a mammalsubject.
 147. The composition of claim 135, wherein the subject has notbeen diagnosed with schizophrenia or bipolar disorder.
 148. Thecomposition of claim 135, further comprising one or more of: lithium,divalproex, antiadherents, binders, coatings, disintegrants, fillers,flavors and colors, glidants, lubricants, preservatives, sorbents andsweeteners.
 149. The composition of claim 135, wherein the salt of theconjugate of quetiapine or an active metabolite and/or an activederivative thereof and an amino acid is a hydrochloride salt, ahydrobromide salt, a hydroiodide salt, a sulfate, a phosphate, anorganic acid salt, a nitrate, a benzoate or a mixture thereof.
 150. Thecomposition of claim 149, wherein the organic acid salt is a mesylatesalt, a besylate salt, a tosylate salt, an oxalate salt, a fumaratesalt, a triflate salt, a citrate salt, a malate salt, or a tartaratesalt.
 151. A composition for treating a psychiatric disorder in asubject comprising, a conjugate of quetiapine or an active metaboliteand/or an active derivative thereof and an amino acid, a salt thereof, aderivative thereof or their combination wherein the composition isrepresented by any one of the following structures of formulas I-IV:

a pharmaceutically acceptable salt thereof, a derivative thereof ortheir combination.
 152. A composition for treating a psychiatricdisorder in a subject comprising, a conjugate of quetiapine or an activemetabolite and/or an active derivative thereof and an amino acid, a saltthereof, a derivative thereof or their combination wherein thecomposition is represented by any one of the following structures offormulas V-VIII:

a pharmaceutically acceptable salt thereof, a derivative thereof ortheir combination.
 153. A method of treating a psychiatric disorderrequiring the binding of dopamine receptor(s), serotonin receptor(s), orboth in a subject, comprising the step of administering to the subject acomposition comprising a therapeutically effective amount of quetiapine,an active metabolite and/or an active derivative thereof, conjugated toan amino acid, a pharmaceutically acceptable salt or derivative thereof,thereby binding a dopamine receptor, a serotonin receptor, or both. 154.The method of claim 153, whereby the amino acid is a standard aminoacid, a non-standard amino acid, a natural amino acid, a synthetic aminoacid or a combination thereof.